Higher Order Structure Analysis of Protein Therapeutics by Covalent Labeling MS

通过共价标记 MS 对蛋白质治疗药物进行高阶结构分析

• 批准号: 9139644
• 负责人: Eric Graban
• 金额: $ 27.73万
• 依托单位: RECLAIM PHARMACEUTICAL WASTE MANAGEMENT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139644
• 关键词: 3-Dimensional; Accounting; Administrator; Amino Acids; Biotechnology; Businesses; Circular Dichroism; Client; Computer software; Data; Data Analyses; Detection; Drug Industry; Effectiveness; Ensure; Exposure to; Fee-for-Service Plans; Feedback; Fluorescence Spectroscopy; Formulation; Generic Drugs; Goals; Healthcare; High Pressure Liquid Chromatography; Higher Order Chromatin Structure; IgG1; Immunoglobulins; Indiana; Indium; Label; Lead; Legal patent; Location; Market Research; Marketing; Mass Spectrum Analysis; Massachusetts; Measurement; Measures; Methods; Molecular Structure; Monoclonal Antibodies; Output; Parents; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Process; Production; Protein Analysis; Protein Engineering; Proteins; Research; Research Personnel; Resolution; Safety; Sales; Sampling; Services; Side; Small Business Innovation Research Grant; Somatropin; Staging; Stress; Structural Genes; Technology; Testing; Therapeutic; Time; Universities; Waste Management; Work; base; cost; design; drug development; drug efficacy; immunogenicity; improved; innovation; insight; light scattering; mass spectrometer; oxidation; patient safety; protein aggregate; protein structure; public health relevance; response; small molecule; success; therapeutic protein; three dimensional structure; tool; user-friendly

 DESCRIPTION (provided by applicant): Protein therapeutics are the fastest growing segment of the pharmaceutical market, accounting for one-third of the overall late stage drug development pipeline, and anticipated to represent 20% of the total pharmaceuticals market value by 2017. However, two significant challenges must be overcome to maximize patient benefit and access to biologic drugs: Patient immunogenicity remains a significant problem for biologic drugs, resulting in patient non-response rates of up to 70% or more over the course of long term treatment. Denatured and aggregated proteins in biologic drugs are a known cause for immunogenicity, so maintaining their 3D structure is therefore critical for ensuring patient safety and drug efficacy. Lack of low cost generic competition looms as a pressing issue with biologic drug patents worth more than $26 billion in annual US sales expiring before 2020. However, one challenge slowing FDA approval of biosimilar drug applications is the inability to ensure that the 3D structures of proposed biosimilars are the same as the original branded drug. Unfortunately, current analytical strategies are inadequate for delivering easy to obtain, high-resolution analyses of protein 3D structure. In response, ReclaimRx and its research partners at Indiana University and University of Massachusetts propose to develop a mass spectrometry method that uses labeling to detect changes in protein 3D structure. This method will be quick, easy to use, and high resolution. Preliminary studies have demonstrated the strong potential for success of the proposed labeling approach by detecting changes in the 3D structure of 3 proteins (β-2-microglobulin, human growth hormone, and immunoglobulin G1) in response to forced degradation conditions. Phase I efforts will build upon this work by demonstrating the feasibility of the proposed technology. This will be achieved through the following Specific Aims: 1) Demonstrate effective detection of the structural degradation of 3 proteins (EPO, human growth hormone, and an IgG1 mAb) in response to thermal and oxidative forced degradation conditions; and 2) Develop a software pipeline specifically designed for protein covalent labeling studies. The simplicity of this approach allows ReclaimRx, an Indiana-based small business, to commercialize this method via a fee-for-service offering, where client will send samples to be analyzed in ReclaimRx's facilities. This service will include data analysis via software that converts the MS files into user-friendly formats. Phase II efforts will focus on developing the technology as a kit that can be purchased to allow researchers to perform the analysis in their own lab, and further refining the software pipeline for commercial use and test conditions relevant to potential customers.

 描述（由适用提供）：蛋白质理论是药物市场增长最快的部分，占整个晚期药物开发管道的三分之一，预计将占2017年总药品总市场价值的20％。但是，到2017年，到2017年，必须克服两个重大挑战，以最大程度地克服患者的益处，以使生物学不合适的问题成为生物学的问题：生物学不合适的问题，是一种生物学的问题。在长期治疗过程中，最多70％或更多。生物药物中的变性蛋白质和聚集的蛋白质是免疫原性的已知原因，因此保持其3D结构对于确保患者的安全和药物效率至关重要。缺乏低成本的通用竞争迫在眉睫，这是一个迫切的问题，即在2020年之前到期的年度销售量超过260亿美元的生物毒品专利。但是，一项挑战减慢了FDA批准生物仿制药物应用的批准是无法确保拟议的生物仿制药的3D结构与原始品牌药物相同。不幸的是，当前的分析策略不足以提供易于获得的蛋白质3D结构的高分辨率分析。作为回应，Reclaimrx及其研究伙伴在印第安纳大学和马萨诸塞大学的提议中开发了一种质谱法，该方法使用标签来检测蛋白质3D结构的变化。此方法将快速，易于使用和高分辨率。初步研究表明，通过检测3种蛋白（β-2-微球蛋白，人类生长马和免疫球蛋白G1）的3D结构的变化来响应强制降解条件，这表明了提出的标记方法成功的强大潜力。第一阶段的努力将通过证明拟议技术的可行性来基于这项工作。这将通过以下特定目的来实现：1）证明有效检测3种蛋白（EPO，人类生长马和IgG1 MAB）的结构降解，以响应热和氧化强迫降解条件； 2）开发专门为蛋白质共价标记研究设计的软件管道。这种方法的简单性允许Reclaimrx（一家基于印第安纳州的小型企业）通过收费服务产品将这种方法商业化，客户将在ReclaimRX的设施中发送样品进行分析。该服务将包括数据分析 通过将MS文件转换为用户友好格式的软件。第二阶段的工作将着重于开发该技术作为套件，可以购买该技术，以使研究人员能够在自己的实验室中进行分析，并进一步完善与潜在客户相关的商业使用和测试条件的软件管道。